Association between antecedent autoimmune diseases and malignancy, including lymphoproliferative disorders (LPD), has been reported in generalized autoimmune diseases such as systemic lupus erythematosus (SLE), dermatomyositis (DM) and rheumatoid arthritis (RA), and also in organ-specific autoimmune diseases such as Sjögren's syndrome (SS) and chronic thyroiditis. In this paper, LPD were summarized for DM, SLE, RA and SS, and some etiologic factors were considered. In surveying previous Japanese literature on the topic, it was revealed that LPD occur frequently in DM similar to various types of cancer. The period between the occurrence of cancer and DM is usually within 12 months, suggesting that the etiologic factor may differ between cancer and LPD in DM. Sixty one cases (20.0%) of monoclonal non-malignant LPD were observed among our 306 patients with SS. Fifteen cases (5.0%) of malignant LPD such as malignant lymphomas (13 cases) and Waldenström's macroglobulinemias (2 cases) were also seen among our SS patients. The activation of rheumatoid factor genes such as Humkv 325 and Vg was considered as one of the triggering factors to advance LPD from the benign to malignant state. A high amount of the bcl-2 protein expression was detected in lymphoepithelial lesions of salivary glands in patients with SS, suggesting that the activation of this gene plays an important role in the progression of the lesion from benign to malignant LPD. Accumulation of many genetic abnormalities including bcl-2 and p 53 genes by chronic stimulation of T and B cells at the site of the autoimmune reaction may be important in the high occurrence of LPD in patients with autoimmune diseases.

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[in Japanese]

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Ligation of B cell antigen receptor (BCR) with antigen or anti-IgM leads to enter cells into the proliferation and differentiation to produce specific Ig. Protein tyrosine kinase (PTK) and CD 45 protein tyrosine phosphatase (PTP) both are involved in the early phase of BCR-mediated B cell signaling. We have investigated the role of p 21^ras (ras) in B cell signal transduction using TNP-specific TA 3 7.9 murine B cells. B cell stimulation with either TNP₆-OVA (Ag) or anti-IgM resulted in rapid accumulation of GTP-bound (active) ras as well as induction of a number of tyrosine phosphorylated substrates. The accumulation of GTP-bound ras was blocked by the treatment with either PTK inhibitors (genistein) or PTP inhibitors (PAO), suggesting that BCR-mediated ras activation is regulated by both PTK and PTP including CD 45. As phosphorylation on tyrosine residues of Lyn, Fyn, and Blk protein tyrosine kinases occurred upon BCR stimulation, these PTKs may be candidates being involved in an induction of not only tyrosine phosphorylation of substrates but also p 21^ras activation. Furthermore we found that rasGAP activity is suppressed following Ag stimulation, accompanied by the phosphorylation on tyrosine of rasGAP and its associated protein p 62. These data indicate that protein tyrosine kinases may alter rasGAP activity to induce p 21^ras activation in B cells.

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CD 46, membrane cofactor protein (MCP), is a membrane regulatory glycoprotein of the complement system, and acts as a cofactor of factor I, which inactivates C 3 b and C 4 b bound on autologous cell membrane. MCP is present on human peripheral blood cells except erythrocytes, fibroblasts, epithelial and endothelial cells, and has been proved to exist in other organs including gastrointestinal tract recently. In this study the expression and characterization of MCP on normal human colonic mucosa was investigated.
Immunohistochemical study showed MCP in the colonic nucosal epithelium. Western blot analysis revealed that MCP protein was expressed as a broad band of 5065 kDa in all cases and another faint band of 4346 kDa in 3 out of 20 cases, though the latter band was highly suspected to be originated from contaminated mononuclear cells in the colon.

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The ratios of CD 11 a, CD 18, HLA-DP on T cells and CD 54 on B cells of 54 patients with active systemic lupus erythematosus (SLE) were examined. The ratios of LFA-1 α, β, ICAM-1, HLA-DP among SLE patients were significantly higher when compared with normal healthy controls, and the significant correlation between the ratio of LFA-1⁺ T cells and HLA-DP⁺ T cells, and LFA-1⁺ T cells and ICAM-1⁺ B cells was recognized.
These results may suggest that LFA-1, ICAM-1 is related to the mutual action between activated T cells and B cells.

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We have already reported that a combination of TNF-alpha and immunogenic variant was effective for immunotherapy of nonimmunogenic tumor. Immunogenic variants (A 2 and A 7) were obtained from nonimmunogenic fibrosarcoma (parent cell: 1767-3) by mutagen treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). In this study, we studied about the possibility of TNF-alpha gene immunotherapy for nonimmunogenic tumor. We established two types of TNF-alpha producing cell lines. One is TNF-alpha producing nonimmunogenic variant (1767 TR 2), and another is TNF-alpha producing immunogenic variant (A 7 TR 3). We compared them about the ability of producing specific immunity against parent tumor. TNF-alpha producing immunogenic variant (A 7 TR 3) could induce strong specific immunity to parental cell compared to TNF-alpha producing nonimmunogenic variant (1767 TR 2). Immunogenicity of tumor is very important when we want to perform TNF-alpha gene immunotherapy against cancer.

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CD 46, membrane cofactor protein, is a glycoprotein widely present on the cell membranes and is different in molecular weight among organs or cells in the same individual. It acts as a cofactor of I of the complement system, which inactivates C 3 b bound to the autologous cells, and protects them from the attack of the complement. In this study CD 46 was demonstrated in the stomach immunochemically. Gastric CD 46 was expressed strongly in the mucosal epithelium, mucosa and endothelial cells of the vessels in the submucosal layer, whereas expressed weakly in the submucosa and muscle. Western blot analyses revealed that gastric CD 46 was expressed as one broad band with molecular weight ranging from 60 kDa to 69 kDa, which was distinct from that of lymphocytes in the peripheral blood.

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Immunoglobulin light chains exist in two distinct forms, as linked to heavy chains by disulfide bonds, and as free light chains (FLc). Neoplastic B-cell disorders are responsible for the major absolute elevations of FLc, which are almost all monoclonal. Free light chains are nephrotoxic, and patients with renal failure have elevated blood concentrations of FLc. Light chains of immunoglobulins have attracted clinical attention as one of the proteins constituting the amyloid fibrils. Moreover, the concept of light chain deposition disease as independent entity has recently been advocated.
In these circumstances TIA nephelometry using commercially available antibodies has been developed for the quantitation of both free kappa and lambda light chains of immunoglobulins in serum. This method is simple and rapid, and enable to analyze a large number of samples at a time, thus the method may be proved to be useful in clinical practice.

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Previous reports have stressed the association between autoimmune disease and lymphoproliferative neoplasm. Here we report a patient in whom multiple myeloma developed about 30 years after the onset of rheumatoid arthritis.
A 79 year-old woman with an about 30-year history of rheumatoid arthritis was admitted because of lumbago in December, 1993. Laboratory findings revealed M-proteinemia (IgA 2, 380mg/dl, IgG 728mg/dl, IgM 51mg/dl) and serum immunoelectrophoresis showed monoclonal IgA with λ type light chain. Bone marrow aspirate contained 66.0% plasma cells. Serological tests of rheumatoid factor were positive. X-ray findings revealed radiolucent myelomatous foci in the skull and typical destructive changes of rheumatoid arthritis in multiple joint. From these findings, IgA λ-type multiple myeloma with rheumatoid arthritis was diagnosed.
Although the pathogenesis of the association between rheumatoid arthritis and multiple myeloma is unkown, prolonged antigenic stimulation manifested by rheumatoid arthritis is considered to be a possible pathogenetic factor in the development of multiple myeloma.

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We report a case of Takayasu arteritis. A woman, 24 years old, was admitted because of fever of unknown etiology. Infection was ruled out. Bruit and asymmetrical pulsation were not found. Ga-scintigram showed abnormal uptake in her upper abdomen. Abdominal echogram revealed neither evidence of abscess nor lymphadenopathy. On abdominal computed tomography, a wall thickening of the abdominal aorta was revealed. In addition, abdominal magnetic resonance imaging (MRI) showed a wall thickening and an enhanced image by gadrinium enhancement. Although we could not carry out conventional aortography because of an allergy to lidocaine, she was diagnosed as having Takayasu arteritis. In response to steroid therapy, the fever promptly dropped and the data indicating inflammation were improved. On the MRI examination after 40 days of steroid therapy, the wall thickening of the abdominal aorta was found to be less prominent. We conclude magnetic resonance imaging is useful for diagnosis and follow-up of early and acute stage of Takayasu arteritis.

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